1. Field of the Invention
The present invention relates to a novel crystal form of glycopyrronium chloride. The present invention also relates to methods of preparing such a crystal form and pharmaceutical compositions which contain such a crystal form. The present invention further relates to methods for the treatment of respiratory diseases by administering such a crystal form.
2. Discussion of the Background
Glycopyrronium bromide (also known as glycopyrrolate) is a muscarinic M3 anticholinergic agent used to reduce salivation associated with administration of certain anaesthetics, and as adjunctive therapy for peptic ulcers. It has also been reported to be effective in the treatment of asthmatic symptoms (Hansel et al., Chest, 2005; 128:1974-1979, which is incorporated herein by reference in its entirety). Glycopyrronium bromide is commercially available, and can be synthesized according to the process described in U.S. Pat. No. 2,956,062, which is incorporated herein in its entirety.
Glycopyrronium bromide has two chiral centers corresponding to four isomeric forms comprising 2 pairs of diastereoisomers, namely (3S,2′R)-, (3R,2′S)-, (3R,2′R)-, and (3S,2′S)-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. Commercially available glycopyrronium bromide consists of the purified “threo” diastereoisomer (3R,2′S) and (3S,2′R). Different pharmacological properties have been attributed to each of the individual isomers of glycopyrronium bromide.
Glycopyrronium bromide has significant stability problems, especially immediately following a conventional micronization process by milling. It is well known that such milling action may induce the generation of amorphous material that can lead to significant instability which appears to be due to the high hygroscopicity of the amorphous fraction. In WO 2006/100453 (which is incorporated herein by reference in its entirety), other counterions, such as iodide, acetate and sulphate salts, have been mentioned as theoretical alternatives to glycopyrronium bromide for overcoming the milling difficulties associated with the latter. No results in terms of stability have anyway been reported.
US 2002/0173536, which is incorporated herein by reference in its entirety, generically discloses further salts including chloride. However, it has been found that also glycopyrronium chloride is hygroscopic.
In view of these considerations, there is still a need of physical stable crystal forms of glycopyrronium salts.